The long term objectives of this application will be to further the understanding of the molecular basis of learning and memory and to apply this knowledge to studies of diseases, such as Alzheimer's Disease. It is widely accepted that the acquisition of long-term memory is a process which depends upon protein synthesis. Hence, it has been postulated that this process is linked to the expression of one or more genes which may be involved in long-term adaptive modifications within the cell. Studies of invertebrate behavior have disclosed that simple forms of learning are characterized by molecular and ionic events with result in changes in synaptic function. Such changes also occur with long-term potentiation (LTP) which has been proposed as a model of neural plasticity and long- term memory processing in the mammalian nervous system. The acquisition of long-term memory bears a striking resemblance to processes which occur during cell growth and differentiation. Therefore, this application will focus on defining the molecular events underlying LTP by examining the level of expression of a proto-oncogene, c-fos. Protooncogenes, such as c-fos, are thought to play a regulatory role in cell growth and differentiation. Hence, it is possible that the heightened neuronal activity associated with LTP is related to c-for induction. We will use c-fos cDNA as a probe and perform Northern blot and in situ hybridization studies to evaluate the level of expression and localize the signal of c- fos message in the rat and rabbit hippocampus during LTP. Immunohistochemical techniques will be conducted to localize Fos protein. In this way, a gene or genes which are important in memory mechanisms and an anatomic substrate of LTP may be identified. Changes in levels of c- fos expression with age will also be studied. It is hoped that these studies will contribute to further understanding of the molecular basis of normal and abnormal cognitive function.